Partial liquid breathing of fluorocarbons

ABSTRACT

The present invention includes a method for treating a patient in need of facilitated oxygen delivery through the lungs, additional lung surfactant, removal of material from inside the lung, or inflation of collapsed portions of the lung, comprising the step of introducing into the lung of the patient an effective therapeutic amount of a fluorocarbon liquid, the amount not exceeding the functional residual capacity of the lung of the patient upon exhalation taking into account any positive and expiratory pressure applied to the patient&#39;s lung. The method may also comprise the additional step of providing an oxygen-containing breathing gas to the patient while the fluorocarbon liquid is in the lung.

This application is a continuation of application U.S. Ser. No.08/299,844, filed Sep. 1, 1994, now U.S. Pat. No. 5,490,498 which is acontinuation of U.S. Ser. No. 07/695,547, filed May 3, 1991, nowabandoned.

FIELD OF THE INVENTION

The present invention relates generally to lung surfactant supplementsand methods for treating pulmonary diseases. The invention specificallydiscloses partial liquid breathing techniques and the use ofbiocompatible liquid fluorocarbons in treatment of various pulmonaryconditions.

BACKGROUND OF THE INVENTION

Lung surfactant is composed of a complex mixture of phospholipid,neutral lipid and protein. Surfactant is roughly 90% lipid and 10%protein with a lipid composition of 55% diphosphotidylcholine (DPPC),25% phosphatidylcholine (PC), 12% phosphatidylglycerol (PG), 3.5%Phosphatidlyethanolamine (PE), sphingomyelin and phosphatidylinositol(PI).

Lung surfactant functions to reduce surface tension within the alveoli.It mediates transfer of oxygen and carbon dioxide, promotes alveolarexpansion and covers the lung surfaces. Reduced surface tension permitsthe alveoli to be held open under less pressure. In addition, lungsurfactant maintains alveolar expansion by varying surface tension withalveolar size (The Pathologic Basis of Disease, Robbins and Cotran eds.W. B. Saunders Co. New York, 1979). There are a number of medicaltherapies or regimes that would benefit from the use of surfactantsupplements. For example, surfactant supplementation is beneficial forindividuals with lung surfactant deficiencies. In addition, there are avariety of medical procedures requiring that fluids be added to thelung, for example, as a wash to remove endogenous or exogenous matter.The use of a biocompatible liquid for these applications would beadvantageous. Routinely, balanced salt solutions or balanced saltsolutions in combination with a given therapeutic agent are provided asan aspirate or as a lavage for patients with asthma, cystic fibrosis orbronchiectasis. While balanced saline is biocompatible, lavageprocedures can remove endogenous lung surfactant. Further, lavage withsuch aqueous liquids may not permit adequate delivery of oxygen to thebody. Therefore, it is contemplated that the use of substances having atleast some of the functional properties of lung surfactant coulddecrease lung trauma and provide an improved wash fluid.

At present, surfactant supplements are used therapeutically when theamount of lung surfactant present is not sufficient to permit properrespiratory function. Surfactant supplementation is most commonly usedin Respiratory Distress Syndrome (RDS), also known as hyaline membranedisease, when surfactant deficiencies compromise pulmonary function.While RDS is primarily a disease of newborn infants, an adult form ofthe disease, Adult Respiratory Distress Syndrome (ARDS), has many of thesame characteristics as RDS, thus lending itself to similar therapies.

Adult respiratory distress occurs as a complication of shock-inducingtrauma, infection, burn or direct lung damage. The pathology is observedhistologically as diffuse damage to the alveolar wall, with hyalinemembrane formation and capillary damage. Hyaline membrane formation,whether in ARDS or RDS, creates a barrier to gas exchange. Decreasedoxygen produces a loss of lung epithelium yielding decreased surfactantproduction and foci of collapsed alveoli. This initiates a vicious cycleof hypoxia and lung damage.

RDS accounts for up to 5,000 infant deaths per year and affects up to40,000 infants each year in the United States alone. While RDS can havea number of origins, the primary etiology is attributed to insufficientamounts of pulmonary surfactant. Those at greatest risk are infants bornbefore the 36th week of gestation having premature lung development.Neonates born at less than 28 weeks of gestation have a 60-80% chance ofdeveloping RDS. The maturity of the fetal lung is assessed by thelecithin/sphingomyelin (L/S) ratio in the amniotic fluid. Clinicalexperience indicates that when the ratio approximates 2:1, the threat ofRDS is small. In those neonates born from mothers with low L/S ratios,RDS becomes a life-threatening condition.

At birth, high inspiratory pressures are required to expand the lungs.With normal amounts of lung surfactant, the lungs retain up to 40% ofthe residual air volume after the first breath. With subsequent breaths,lower inspiratory pressures adequately aerate the lungs since the lungsnow remain partially inflated. With low levels of surfactant, whether ininfant or adult, the lungs are virtually devoid of air after eachbreath. The lungs collapse with each breath and the neonate mustcontinue to work as hard for each successive breath as it did for itsfirst. Thus, exogenous therapy is required to facilitate breathing andminimize lung damage.

Type II granular pneumocytes synthesize surfactant using one of twopathways dependent on the gestational age of the fetus. The pathway useduntil about the 35th week of pregnancy produces a surfactant that ismore susceptible to hypoxia and acidosis than the mature pathway. Apremature infant lacks sufficient mature surfactant necessary to breatheindependently. Since the lungs mature rapidly at birth, therapy is oftenonly required for three or four days. After this critical period thelung has matured sufficiently to give the neonate an excellent chance ofrecovery.

In adults, lung trauma can compromise surfactant production andinterfere with oxygen exchange. Hemorrhage, infection, immunehypersensitivity reactions or the inhalation of irritants can injure thelung epithelium and endothelium. The loss of surfactant leads to foci ofatelectasis. Tumors, mucous plugs or aneurysms can all induceatelectasis, and these patients could therefore all benefit fromsurfactant therapy.

In advanced cases of respiratory distress, whether in neonates oradults, the lungs are solid and airless. The alveoli are small andcrumpled, but the proximal alveolar ducts and bronchi are overdistended.Hyaline membrane lines the alveolar ducts and scattered proximalalveoli. The membrane consists of protein-rich, fibrin-rich edemaadmixed with cellular debris.

The critical threat to life in respiratory distress is inadequatepulmonary exchange of oxygen and carbon dioxide resulting in metabolicacidosis. In infants this, together with the increased effort requiredto bring air into the lungs, produces a lethal combination resulting inoverall mortality rates of 20-30%.

Optimally, surfactant supplements should be biologically compatible withthe human lung. They should decrease the surface tension sufficientlywithin the alveoli, cover the lung surface easily and promote oxygen andcarbon dioxide exchange.

Ventilation assistance is commonly used to provide sufficient oxygen tosurfactant deficient patients. These ventilation regimes includecontinuous positive airway pressure, or continuous distending pressureprocedures.

Recently, surfactant replacement therapy has been used either alone orin combination with ventilation therapy. Initial work with surfactantreplacements used preparations of human lung surfactant obtained fromlung lavage. The layaged fluid is collected and the surfactant layernaturally separates from the saline wash. This layer is harvested andpurified by gradient centrifugation. These preparations worked well assurfactant replacements for RDS and thus provided some of the originaldata to suggest that surfactant replacement was a necessary therapy.Supplies of human surfactant are limited and expensive, and thereforealternate sources of surfactant were investigated for use in replacementtherapies.

The second generation of surfactant substitutes are purifiedpreparations of bovine and porcine lung surfactant. Preparations ofbovine lung surfactant have been administered to many surfactantdeficient patients. Like human surfactant, bovine lung surfactant isdifficult to prepare. Sources are few and availability is limited.Further, while the use of bovine lung surfactant in neonares does notpresent a problem immunologically, bovine surfactant applications inadults could immunologically sensitize patients to other bovineproducts.

To minimize the immunologic problems associated with the use of bovinelung surfactant, the harvested surfactant is further extracted withchloroform/methanol to purify the lipid component. This work led to thediscovery that there are three major proteins (SP-A, SP-B and SP-C)associated with lung surfactant. All three are postulated to have somebeneficial role in surfactant function. SP-A is hydrophobic and has somedocumented antibacterial activity. SP-B is most closely associated withtraditional surfactant function. These proteins can be purified orcloned, expressed and added back to purified lipid preparations.However, these procedures are also time consuming. In addition, the useof purified animal-derived surfactant protein creates the sameimmunologic problems noted above.

Some of the functional domains within each of the surfactant proteinsare now mapped and the individual lipid components of lung surfactantare being tested to determine if a semi-synthetic or synthetic productcan be used effectively to replace purified endogenous surfactant. Tothis end, synthetic peptides of SP-B have been added to mixtures of DPPCand PG to create an artificial surfactant product.

An artificial surfactant would readily cover the lung surfaces andfacilitate oxygen exchange. The surfactant would be sterilizable,amenable to large scale production and be relatively stable forconvenient storage and physician convenience.

Fluorocarbons are fluorine substituted hydrocarbons that have been usedin medical applications as imaging agents and as blood substitutes. U.S.Pat. No. 3,975,512 to Long uses fluorocarbons, including brominatedperfluorocarbons, as a contrast enhancement medium in radiologicalimaging. Brominated fluorocarbons and other fluorocarbons are known tobe safe, biocompatible substances when appropriately used in medicalapplications.

It is additionally known that oxygen, and gases in general, are highlysoluble in some fluorocarbons. This characteristic has permittedinvestigators to develop emulsified fluorocarbons as blood substitutes.For a general discussion of the objectives of fluorocarbons as bloodsubstitutes and a review of the efforts and problems in achieving theseobjectives see "Reassessment of Criteria for the Selection ofPerfluorochemicals for Second-Generation Blood Substitutes: Analysis ofStructure/Property Relationship" by Jean G. Reiss, Artificial Organs8:34-56, 1984.

Oxygenarable fluorocarbons act as a solvent for oxygen. They dissolveoxygen at higher tensions and release this oxygen as the partialpressure decreases. Carbon dioxide is handled in a similar manner.Oxygenation of the fluorocarbon when used intravascularly occursnaturally through the lungs. For other applications, such aspercutaneous transluminal coronary angioplasty, stroke therapy and organpreservation, the fluorocarbon can be oxygenated prior to use.

Liquid breathing has been demonstrated on several occasions. An animalmay be submerged in an oxygenated fluorocarbon liquid and the lungs maybe filled with fluorocarbon. Although the work of breathing is increasedin these total submersion experiments, the animal can derive adequateoxygen for survival from breathing the fluorocarbon liquid.

Liquid breathing as a therapy presents significant problems. Liquidbreathing in a hospital setting requires dedicated ventilation equipmentcapable of handling liquids. Moreover, oxygenation of the fluorocarbonbeing breathed must be accomplished separately. The capital costsassociated with liquid breathing are considerable.

It is an object of the present invention to provide a method fortreating lung surfactant deficiency through use of fluorocarbon liquids.

A further object of the invention is to provide a method for therapeuticuse of fluorocarbon liquids in the lungs that does not requireliquid-handling ventilation equipment. Instead, traditional gasventilation equipment can be used.

Still a further object of the present invention is to apply pulmonaryadministration of fluorocarbon liquids to a wide range of diseases andmedical conditions.

These and other objects of the invention are discussed in the detaileddescription of the invention that follows.

SUMMARY OF TEE INVENTION

The present invention includes a method for treating a patient in needof facilitated oxygen delivery through the lungs, additional lungsurfactant, removal of material from inside the lung, or inflation ofcollapsed portions of the lung, comprising the step of introducing intothe lung of the patient an effective therapeutic amount of afluorocarbon liquid, the amount not exceeding the functional residualcapacity of the lung of the patient upon exhalation taking into accountany positive and expiratory pressure applied to the patient's lung. Themethod may also comprise the additional step of providing anoxygen-containing breathing gas to the patient while the fluorocarbonliquid is in the lung.

In addition, a patient in need of additional lung surfactant may receivethe fluorocarbon liquid as a lung surfactant replacement. In a preferredembodiment the amount of fluorocarbon liquid introduced into the lungsis at least about 0.1% of the patient's total lung capacity and not morethan about 50% of the patient's total lung capacity, wherein the totallung capacity comprises the fluid volume of the lung when fully inflatedduring normal breathing. A preferred fluorocarbon is a brominatedfluorocarbon and a still more fluorocarbon is perfluorooctylbromide. Itis additionally contemplated that the equilibrium coefficient ofspreading of the fluorocarbon is a positive number and more preferablythat the equilibrium coefficient of spreading of the fluorocarbon be atleast 1.0.

The amount of fluorocarbon liquid introduced into the patient's lung iscontemplated to be at least 0.1 ml/kg of the patient's body weight andnot more than about 50 ml/kg patient body weight.

It is further contemplated that the respiration of the patient while thefluorocarbon is in the lung can be facilitated by external ventilationequipment. In addition, it is contemplated that fluorocarbons can beused for partial liquid ventilation in patients having a respiratorydistress syndrome and further that the method is effective to alleviatethe respiratory distress syndrome. Another preferred use of fluorocarbonin the lung comprises the use of fluorocarbons for patients in need ofremoval of material from inside the lung, comprising the step ofremoving the fluorocarbon liquid, together with the material, from thelung. An additional method for the removal of material from the lung,comprises the steps of permitting the material to float on thefluorocarbon, and removing the floating material from the lung.

Fluorocarbon liquid can additionally be administered in combination witha hydrophilic pharmacologic agent in particulate form. It is furthercontemplated that the pharmacologic agent is a hydrophilic lungsurfactant in powdered form. In addition, fluorocarbon is provided topatients in need of facilitated oxygen delivery through the lungs andfor those patients receiving oxygen-containing breathing gas, it iscontemplated that the oxygen containing breathing gas is oxygen.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphic representation of the effect of intratrachealperfluorooctylbromide instillation of the blood oxygen levels in rabbitsfollowing lung lavage to remove endogenous surfactant as compared withintratracheal saline instillation.

FIG. 2 is a graphic representation of the effect of intratrachealperfluorooctylbromide instillation on blood carbon dioxide levels inrabbits following lung lavage to remove endogenous surfactant.

FIG. 3 is a graphic representation of the effect of intratrachealperfluorooctlybromide instillation on mean and peak lung airwaypressures in rabbits following lung lavage to remove endogenoussurfactant.

DETAILED DESCRIPTION OF THE INVENTION

As noted, lung surfactant supplements should be non-toxic andbiologically compatible. Like human surfactant, surfactant supplementsshould decrease the surface tension within the alveoli and promoteoxygen and carbon dioxide exchange. Additionally these substitutesshould spread easily over the lung surfaces to maximize gas interchange.Such a surfactant would enhance gas exchange, thus reducing cyanosis andmetabolic acidosis.

Surfactant replacements that do not spread easily within the lung willtend to concentrate in pools and be less than optimally effective.Surfactant supplements should be readily available to the physician. Inaddition, they should be provided as a sterile product having reasonablechemical stability and a sufficient shelf-life.

Compounds useful in this invention, such as those listed below(hereinafter called "fluorocarbons") are generally able to promote gasexchange, and most of these fluorocarbons readily dissolve oxygen andcarbon dioxide. There are a number of fluorocarbons that arecontemplated for medical use. These fluorocarbons include bis (F-alkyl)ethanes such as C₄ F₉ CH=CH₄ CF₉ (sometimes designated "F-44E"), i-C₃ F₉CH=CHC₆ F₁₃ ("F-i36E"), and C₆ F₁₃ CH=CHC₆ F₁₃ ("F-66E"); cyclicfluorocarbons, such as C10F18 ("F-decalin", "perfluorodecalin" or"FDC"), F-adamantane ("FA"), F-methyladamantane ("FMA"),F-1,3-dimethyladamantane ("FDMA"), F-di-orF-trimethylbicyclo[3,3,1]nonane ("nonane"); perfluorinated amines, suchas F-tripropylamine ("FTPA") and F-tri-butylamine ("FTBA"),F-4-methyloctahydroquinolizine ("FMOQ"),F-n-methyl-decahydroisoquinoline ("FMIQ"), F-n-methyldecahydroquinoline("FHQ"), F-n-cyclohexylpurrolidine ("FCHP") and F-2-butyltetrahydrofuran("FC-75" or "RM101").

Other fluorocarbons include brominated perfluorocarbons, such as1-bromo-heptadecafluoro-octane (C₈ F₁₇ Br, sometimes designatedperfluorooctylbromide or "PFOB"), 1-bromopentadecafluoroheptane (C₇ F₁₅Br), and 1-bromotridecafluorohexane (C₆ F₁₃ Br, sometimes known asperfluorohexylbromide or "PFHB"). Other brominated fluorocarbons aredisclosed in U.S. Pat. No. 3,975,512 to Long. Also contemplated arefluorocarbons having nonfluorine substituents, such as perfluorooctylchloride, perfluorooctyl hydride, and similar compounds having differentnumbers of carbon atoms. In addition, the fluorocarbon may be neat ormay be combined with other materials, such as surfactants (includingfluorinated surfactants) and dispersed materials.

Additional fluorocarbons contemplated in accordance with this inventioninclude perfluoroalkylated ethers or polyethers, such as (CF₃)₂ CFO(CF₂CF₂)₂ OCF(CF₃)₂, (CF₃)₂ CFO-(CF₂ CF₂)₃ OCF(CF₃), (CF₃)CFO(CF₂ CF₂)F,(CF₃)₂ CFO(CF₂ CF₂)₂ F, (C₆ F₁₃)₂ O. Further, fluorocarbon-hydrocarboncompounds, such as, for example compounds having the general formulaC_(n) F_(2n+1) -C_(n') F_(2n'+1), C_(n) F_(2n+1) OC_(n') F_(2n'+1), orC_(n) F_(2n+1) CF=CHC_(n') F_(2n'+1), where n and n' are the same ordifferent and are from about 1 to about 10 (so long as the compound is aliquid at room temperature). Such compounds, for example, include C₈ F₁₇C₂ H₅ and C₆ F₁₃ CH=CHC₆ H₁₃.It will be appreciated that esters,thioethers, and other variously modified mixed fluorocarbon-hydrocarboncompounds are also encompassed within the broad definition of"fluorocarbon" materials suitable for use in the present invention.Mixtures of fluorocarbons are also contemplated. Additional"fluorocarbons" not listed here, but having those properties describedin this disclosure that would lend themselves to pulmonary therapies areadditionally contemplated.

Some fluorocarbons have relatively high vapor pressures which renderthem less suitable for use as a surfactant replacement and for partialliquid breathing. These include 1-bromotridecafluorohexane (C₆ F₁₃ Br)and F-2-butyltetrahyddrofuran ("FC-75" or "RM101"). Lower vaporpressures are additionally important from an economic standpoint sincesignificant percentages of fluorocarbon having high vapor pressure wouldbe lost due to vaporization during the therapies described herein. In apreferred embodiment, fluorocarbons having lower surface tension valuesare chosen as surfactant supplements.

The fluorocarbon of choice should have functional characteristics thatwould permit its use temporarily as a lung surfactant, for oxygendelivery, in removal of material from the interior of the lung, or forinflation of collapsed portions of the lung. Fluorocarbons arebiocompatible and most are amenable to sterilization techniques. Forexample, they can be heat-sterilized (such as by autoclaving) orsterilized by radiation. In addition, sterilization by ultrafiltrationis also contemplated.

One group of preferred fluorocarbons have the ability to reduce thesurface tension in the lung. As noted above, surfactants function todecrease the tension between the surface molecules of the alveolarfluid. The lung surfactant is solubilized in a water-continuous fluidlining the alveolus. Typically, the surface tension in the absence oflung surfactant is ca. 60 dynes/cm decreasing to 5-30 dynes/cm in thepresence of lung surfactant. Fluorocarbons have low surface tensionvalues (typically in the range of 20 dynes/cm) and have the addedbenefit of dissolving extremely large quantities of gases such as oxygenand carbon dioxide. Perfluorocarbons are particularly suited for thisuse, and brominated fluorocarbons are particularly preferred.

Although reduction in surface tension is an important parameter injudging fluorocarbons and perfluorocarbons as potential lung surfactantsupplements or for use in partial liquid breathing, a novel andnon-obvious characteristic of some fluorocarbons is their apparentability to spread over the entire respiratory membrane. The ability ofsome fluorocarbons to spread evenly and effectively over lung surfacesmay be of even greater importance than the ability of fluorocarbons toreduce surface tension.

The total surface area of the respiratory membrane is extremely large(ca. 160 square meters for an adult). Thus, an effective fluorocarbonfor partial liquid breathing should be able to cover the lung surfaceswith relatively little volume.

The ability of a given substance to cover a measured surface area can bedescribed by its spreading coefficient. The spreading coefficients forfluorocarbons can be expressed by the following equation:

    S(o on w)=γ.sub.w/a -(γ.sub.w/o +γ.sub.o/a)

Where S (o on w) represents the spreading coefficient; γ=interfacialtension; w/a=water/air; w/o=water/oil; and o/a=oil/air.

If the fluorocarbon exhibits a positive spreading coefficient, then itwill spread over the entire surface of the respiratory membranespontaneously. Fluorocarbons having spreading coefficients of at leastone are particularly preferred. If the spreading coefficient isnegative, the compound will tend to remain as a lens on the membranesurface. Adequate coverage of the lung surface is important forrestoring oxygen and carbon dioxide transfer and for lubricating thelung surfaces to minimize further pulmonary trauma.

The spreading coefficients for a number of perfluorocarbons are reportedin Table 1. Each perfluorocarbon tested is provided together with itsmolecular weight and the specific variables that are used to calculatethe spreading coefficient S (o on w). The perfluorocarbons reported arePFOB, perfluorotributylamine (FC-17), perfluorodecalin (APF-140),dimethyl perfluorodecalin (APF-175), trimethyl decalin (APF-200),perfluoroperhydrophenanthrene (APF-215 ), pentamethyl decal in(APF-240), and octamethyl decalin (APF-260).

These perfluorocarbons are representative of groups of perfluorocarbonshaving the same molecular weight that would produce similar spreadingcoefficients under similar experimental conditions. For example, it isexpected that ethyl perfluorodecalin will have a spreading coefficientsimilar to that of dimethylperfluorodecalin. Propyl or other 3carbon-substituted decalin would have a spreading coefficient similar tothat reported for trimethyl decalin, pentamethyldecalin isrepresentative of other decalins substituted with 5 substituent carbons,and octamethyldecalin is also representative of other combinationsubstituted decalins of identical molecular weight.

                  TABLE I                                                         ______________________________________                                        Spreading coefficients of perfluorocarbons on saline (T = 25 C)                            MW       γ.sub.o/a                                                                        γ.sub.o/w                                                                      S                                       Perfluorocarbon                                                                            (g/mol)  (mN/m)   (mN/m) (o on w)                                ______________________________________                                        PFOB         499      18.0     51.3   +2.7                                    (perfluorooctylbromide)                                                       FC-47        671      17.9     55.1   -1.0                                    (perfluorotributylamine)                                                      APF-140      468      18.2     55.3   -1.5                                    (perfluorodecalin)                                                            APF-175      570      20.7     55.9   -4.6                                    (dimethyl decalin)                                                            APF-200      620      21.4     55.9   -5.3                                    (trimethyl decalin)                                                           APF-215      630      21.6     56.0   -5.6                                    (perfluoroperhydrophenanthrene)                                               APF-240      770      22.6     56.3   -6.9                                    (pentamethyl decalin)                                                         APF-260      870      22.4     56.1   -6.5                                    (octamethyl decalin)                                                          ______________________________________                                    

It can be seen from this limited sampling of fluorocarbons thatperfluorooctylbromide (PFOB) provides a positive spreading coefficient.In addition, PFOB has a low vapor pressure (14 tort @ 37° C.), furtherillustrating that PFOB is a particularly preferred choice for use as alung surfactant replacement. Because of the reduced vapor pressure, PFOBwill have a decreased tendency to vaporize during use. Perfluorodecalin(APF-140) and perfluoroamine (FC-47) have also been tested in potentialblood substitute formulations. These compounds exhibit negativespreading coefficients on saline. However, other perfluorocarbons,similar to APF-140 and FC-47, but having decreasing molecular weights,exhibited decreasing surface tensions and increasing spreadingcoefficients. This suggests that lower molecular weight perfluorocarbonsmight also have useful spreading coefficients. However, decreasingmolecular weight will increase vapor tension and make the compounds lesssuitable for this use.

The following examples provide information relating to the effect ofPFOB treatment on respiratory insufficiency in an experimental rabbitmodel. The general protocol for partial liquid ventilation of therabbits is described below.

Animal Preparation

New Zealand rabbits weighing between 2.8 and 3.0 kg were anesthetizedwith 50 mg/kg of phenobarbital sodium iv and a cannula was insertedthrough a tracheotomy midway along the trachea with its tip proximal tothe carina. Ventilation with a Servo ventilator 900C (Siemens-Elema,Sweden) was initiated using pure oxygen and zero end-expiratory pressurewith a constant tidal volume of 12 ml/kg, frequency of 30/min andinspiratory time of 35%. Anesthesia was maintained with additional dosesof pentobarbital, as required, and pancuronium bromide was administeredas an intravenous bolus (0.1 mg/kg) and followed by a continuousinfusion (0.1 mg/kg/hr) for muscle paralyzation. A solution of 5%dextrose and 0.45% NaCl was administered continuously at a rate of 10ml/kg/hr as a maintenance fluid. A heating pad maintained coretemperature at 37°±1° C., monitored by an esophageal thermistor(Elektroalboratoriet, Copenhagen).

Left femoral artery and vein were each cannulated with polyvinylcatheters for arterial and central venous pressure recording and bloodsampling. A special indwelling catheter (Mikro-pO₂ -Messkatheter, Licox)was inserted into the right femoral artery for continuous oxygenpressure monitoring (Licox, GMS, Germany). Arterial blood gas and Hb(hemoglobin) measurements were made by Osm-2 Hemoximeter and ABL-330(Radiometer Copenhagen). Lung mechanics and endtidal CO₂ were measuredby means of Lung Mechanics Calculator 940 (Siemens-Elema, Sweden) andCO₂ Analyzer 930 (Siemens-Elema, Sweden), respectively. Intravascularpressure monitoring was made by using a Statham P23XL transducer(Spectramed, USA) and all tracings including ECG were recorded by aSirecust 1280 recorder (Siemens).

Model of Respiratory Insufficiency

After the control observations were made, lung lavage with 30ml/kg ofwarm saline (37° C.) was performed to induce respiratory insufficiency.After the first lavage, positive end expiratory pressure (PEEP) wasincreased to 6 cmH₂ O and lung layages were repeated to get an arterialpO₂ below 100 mmHg with the initial ventilatory settings (between 4-6layages). The same ventilation mode was used throughout the experiment(volume control ventilation; F_(i) O₂ :1, tidal volume: 12 ml/kg, PEEP:6 cm H₂ O, frequency: 30/min, inspiratory time: 35%).

Partial Liquid Ventilation Procedure

After respiratory insufficiency was induced, PFOB liquid wasadministered through the tracheal cannula into the animal's lungs withincremental doses of 3 ml/kg up to a total volume of 15 ml/kg. Animalswere ventilated for 15 minutes after each dose of PFOB instillation withthe same ventillatory settings as mentioned above and thereafterarterial blood gases, cardiocirculatory parameters and pulmonarymechanics were measured. After the last dose PFOB measurements, animalswere sacrificed by administration of high dose pentobarbital.

EXAMPLE 1

Mean Arterial Oxygen Tensions Following PFOB Administration

FIG. 1 is a graphic representation of the results of the experimentalprotocol described above. The mean arterial oxygen tension in the sixrabbits tested was 504.2 mmHg. Following lung lavage to removesurfactant the arterial oxygen tension dropped to a mean value of 75.1mmHg. The administration of increasing volumes of PFOB resulted inincreasing arterial oxygen tensions. Doses of 15 ml/kg of PFOB increasedoxygen pressures to 83% of their original value. These results arecompared to the use of saline for partial liquid ventilation. Increasingvolumes of saline in place of PFOB yielded an additional drop inarterial oxygen pressure. This data indicates that the administration ofthe perfluorocarbon PFOB significantly improved the arterial oxygentension in the experimental animals as compared to saline treatedcontrols.

EXAMPLE 2

Mean Arterial Carbon Dioxide Tensions Following PFOB Administration

Mean arterial carbon dioxide tensions were calculated following lunglavage using the experimental protocol described above. FIG. 2 is agraphic representation of these results. Before lavage the averagearterial carbon dioxide tensions in the lungs was 37 mmHg. Following thelavage procedure the carbon dioxide levels increased to 48.7 mmHg. Thislevel decreased after administration of PFOB, indicating that CO₂transport was also facilitated by PFOB administration.

EXAMPLE 3

Mean Airway Pressures Following PFOB Administration

Mean airway pressures were determined following PFOB supplementation ofsurfactant deficient animals. FIG. 3 shows mean airway pressuresmeasured in cmH₂ O as a function of increasing volumes of PFOB added.Following lung lavage the airway pressures increased due to surfactantdepletion. PFOB supplementation decreased mean airway pressure.

The data for Examples 1-3 are provided in Table 2.

    ______________________________________                                                    INTRATRACHEAL PFOB ml/kg                                                 BEFORE                                                                        LAVAGE ARDS    3      6    9    12   15                                ______________________________________                                        P.sub.a O.sub.2 mmHg                                                          X        504.2    75.1    159.6                                                                              296.7                                                                              365.7                                                                              398.2                                                                              419.9                           SD       39.7     15.0    38.1 54.4 33.4 35.7 27.3                            P.sub.a CO.sub.2 mmHg                                                         X        37.0     48.7    42.8 44.4 45.0 44.8 45.5                            SD       2.6      6.0     4.7  4.8  4.6  4.8  4.4                             Peak Airway                                                                   Pressure                                                                      cmH.sub.2 O                                                                   X        12.4     25.5    21.3 20.6 20.6 20.6 21.1                            SD       1.4      1.0     1.4  1.2  1.6  1.5  1.4                             ______________________________________                                    

Both fetal and adult rabbits have been used to study RespiratoryDistress Syndrome. Much of the work with surfactant replacements wasinitiated in these animals. For studies on RDS therapies, the method offetal animal ventilation used should closely mimic the ventilationmethods used for the neonate. Other fetal and adult animals studiedinclude lamb, dog or baboon. In vivo studies in animals are necessary tocorrelate the in vitro characteristics of a given fluorocarbon with itsin vivo benefits.

An analysis of the therapeutic benefit or the usefulness of a givenfluorocarbon or a lung additive containing fluorocarbon necessarilyincludes an analysis of a number of experimental parameters. Theseparameters include measurements of dynamic lung compliance, blood gasquantitations, alveolar/arterial oxygen tension ratios, lung waterestimates, vascular protein leakage into the lung, inflammatory cellinfiltrates, chest radiographs, ventilatory support indices over timeand the like. Lung histologies from experimental subjects are used todemonstrate the resolution of atelectasis, evidence of necrosis,desquamation and inflammation. Individuals skilled in the art will befamiliar with the test parameters listed above, therefore no furtherinformation needs be provided to facilitate these tests. Fluorocarbonsproviding beneficial test results in experimental animals are candidatesfor human use.

It is contemplated that there are a variety of uses for fluorocarbons inpartial liquid breathing applications. Lung lavage can be used as both adiagnostic and therapeutic procedure. Diagnostic washings are oftenobtained by bronchoscopy. Diagnostic lavage requires the introduction ofa small amount of fluid into the lungs in order to sample lung cells,exudate, or to obtain a sample for microbiological analysis.

Therefore, in accordance with one aspect of this invention, it iscontemplated that PFOB or another fluorocarbon meeting the positivecriteria disclosed herein could be used for such a procedure.

Large volume lung lavage is sometimes used as an emergency procedure toremove irritants, poisons or mucous plugs from the lungs. The procedureis also used in neonates to remove aspirated meconium. A pulmonarycatheter is inserted into the bronchial airway and a solution is flushedinto the lung. The use of saline in the lung for large volume lavagecreates several problems. The procedure must be performed quicklybecause oxygen transfer at the membrane/air interface cannot occurefficiently in the presence of saline, and large volumes of salineflushed into the lungs effectively dilute and remove any functional lungsurfactant present.

It is also contemplated that fluorocarbons could be used to inflatecollapsed portions of lungs or collapsed lungs in general. The use offluorocarbon to inflate portions of the lung is less damaging than thecurrent methods employing increased air pressure. As noted previously,increased air pressures in lungs, particularly lungs that arecompromised by disease or trauma, can produce barotrauma and induceadditional lung damage.

If the lungs have been compromised by an irritant then surfactantreplacement may be necessary. Oxygenatable fluorocarbons with positivespreading coefficients and low vapor pressures could provide an improvedlavage fluid.

The fluorocarbon could also be provided as a liquid or aerosol incombination with an expectorant. The biocompatible fluorocarbon iseasily taken into the lung and the expectorant additive facilitates theremoval of the secretions of the bronchopulmonary mucous membrane.Examples of contemplated expectorants include but are not limited toammonium carbonate, bromhexine hydrochloride and terpin hydrate.

In accordance with another aspect of this invention, it is furthercontemplated that PFOB or another suitable fluorocarbon could be used asa surfactant supplement. PFOB is able to spread easily over the surfacesof the lung and can facilitate oxygen transport. Any conditioncharacterized by a lung surfactant deficiency would be amenable to thistherapy. In addition to RDS in neonates, ARDS in adults caused by severehypovolemic shock, lung contusion, diver's lung, post-traumaticrespiratory distress, post-surgical atelectasis, septic shock, multipleorgan failure, Mendelssohn's disease, obstructive lung disease,pneumonia, pulmonary edema or any other condition resulting in lungsurfactant deficiency or respiratory distress are all candidates forfluorocarbon supplementation.

The amount of surfactant supplement given should be sufficient to coverthe lung surface and should be at least 0.1% of the infant or adult'stotal lung capacity. In RDS, it is particularly important to stabilizethe infant while minimizing and preventing additional lung damage forroughly four or five days. Those infants with RDS that survive thiscritical time frame have an 80% survival rate. The fluorocarbon isprovided by direct instillation through an endotracheal tube. If thefluorocarbon is provided together with a surfactant powder, the powdercan either be mixed into the fluorocarbon or provided to the infant oradult as an aerosol prior to fluorocarbon administration. The additionof lung surfactant powder to fluorocarbon provides a surfactantparticulate dispersed throughout the fluorocarbon liquid.

During administration, the infant is placed in the right and leftlateral decubitus positions while being mechanically or manuallyventilated. Chest radiographs reveal that unlike other surfactantreplacements in use that lack positive spreading coefficients,fluorocarbon is unilaterally distributed in the chest cavity. Sinceneonares are often difficult to intubate, only those individualsexperienced in neonatal intubation should attempt this procedure.Mechanical ventilator usage and initial settings of breaths/minute,positive inspiratory pressures, positive-end expiratory pressure andinspiratory durations should be set initially as determined by the knownstandards for given infant weight and gestational ages, but should bemonitored closely and altered accordingly as pulmonary functionimproves.

The use of partial liquid breathing is not restricted to cases wherelung surfactant supplementation is necessary. Any condition requiringfacilitated oxygen delivery, for example, is amenable to use of partialliquid breathing. Because the volume of fluorocarbon in the lung is suchthat liquid fluorocarbon is not exhaled by the patient, conventionalventilation equipment can be used. This overcomes a major obstacle toliquid breathing as contemplated in the prior art.

In addition to oxygen delivery, fluorocarbons can be used to removeendogenous or foreign material from the interior of the lungs. Lavagecan be practiced using fluorocarbons as a substitute for conventionalsaline solutions. In this procedure, oxygen is provided to the patientby the fluorocarbon liquid itself, permitting a more lengthy and lessdangerous lavage procedure. Moreover, removal of lung surfactant throughthe lavage is not a major problem because of the lung surfactantproperties of selected fluorocarbons. The lavage procedure is furtherfacilitated by the density of the fluorocarbon. The density of theseliquids is generally 2, that is, twice that of water; they thereforetend to displace the material to be removed. This material can then beremoved by removing the fluorocarbon, or can be removed from the surfaceof the fluorocarbon on which it will generally float.

In addition to the lung surfactant properties, the density of thefluorocarbon can facilitate inflation of collapsed alveoli and otherportions of the lung. Under the influence of gravity, the fluorocarbonwill apply positive pressure above and beyond breathing pressure toinflate such collapsed portions of the lung.

The use of fluorocarbons for partial liquid breathing requires a volumeas little as 0.1% of the total lung capacity upon full naturalinflation. However, it is preferred that the amount used be at least0.2%, and more preferably at least 0.3% or 0.5% of the total lungcapacity. Minimum amounts of 1%, 3%, or 5% of total lung capacity arepreferred. It is additionally contemplated that fluorocarbon could beadded in amounts up to about 50% of the total lung capacity.

Thus a method for partial liquid breathing is provided as another aspectof this invention.

Partial liquid breathing has a number of benefits over the total liquidbreathing methods contemplated primarily for use in neonares. It appearsthat the difficult transition from total liquid breathing to total airbreathing can be reduced by partial liquid breathing. The lungs arebathed in a biocompatible fluid. Lung trauma is minimized and thispermits lung maturation and repair. Partial liquid breathing is moreamenable to use in adults than total liquid breathing since air or gascan still be inhaled and exhaled. Partial liquid breathing can be usedin conjunction with spontaneous, passive or mechanical ventilation. Inaddition, pharmacologic substances can be added to the fluorocarbon tofurther promote resolution of lung injury.

The amount of fluorocarbon introduced into the patient's lung is, at aminimum, necessarily sufficient to cover the surfaces of the lung. Theactual volumes will depend on the treatment protocol, the weight andsize of a patient as well as the lung capacity. It is contemplated thatthe useful range of fluorocarbon should be at least 0.1 ml offluorocarbon liquid per kilogram patient body weight and not more thanabout 50 ml/kg.

It is further preferred that the maximum amount of fluorocarbon used forpartial liquid breathing will approximate the volume of air remaining ina healthy lung of similar size following exhalation. The amount of airremaining in the lung at the end of exhalation can be measured in anumber of ways that are known by those with skill in the art.Physiology-related equations relate the size, age, or weight of anindividual to his exhaled lung volume.

Thus, during partial liquid breathing in accordance with the presentinvention, the lungs retain sufficient air capacity (above and beyondthe volume of fluorocarbon in the lung) to permit inhalation such thatnormal breathing can proceed. The amount of air entering the lungs oninhalation is sufficient to oxygenate the fluorocarbon liquid. Further,the fluorocarbon liquid may be oxygenated prior to use to provide oxygento the alveolar surfaces of the lung instantaneously upon initialcontact with the fluorocarbon. If ventilation therapy is required,unlike total liquid breathing, standard ventilation equipment can beused. Partial liquid breathing can be used to reverse ventilary failure,as a prophylactic to prevent respiratory failure or as a therapeutic. Asa therapeutic, fluorocarbon solution can be administered alone tominimize further lung trauma, or in combination with a given therapeuticagent. Fluorocarbon liquid can be provided together with a particulatetherapeutic agent such as lung surfactant. These powder surfactants maybe synthetic mixtures of phospholipids. For example, a mixture ofdiphosphatidylcholine and phosphoglycerol in a ratio of 7:3 could bemixed with a volume of fluorocarbon. Additionally, the surfactant powdermay be in the form of dried extracts prepared from human or animal lunglavage. It was noted earlier that there are three major proteins (SP-A,SP-B and SP-C) associated with endogenous lung surfactant. Therefore, itis additionally contemplated that these proteins may be added as fulllength or as truncated fragments to the fluorocarbon mixture.

Partial liquid breathing according to the present invention is usefulfor a variety of medical applications. As a lavage, the technique isuseful for meconium aspiration, gastric acid aspiration, asthma, cysticfibrosis, and pneumonia to remove adventitious agents. A fluorocarbonlavage may also be provided to patients with pulmonary alveolarproteinosis, bronchiectasis, atelectasis and immotile cilia syndrome. Inaddition, fluorocarbon may be used in emergency lavage procedures toremove food aspirates and other foreign materials.

Loss of lung resiliency can occur in both ARDS and RDS. The use offluorocarbons in both of these syndromes is discussed above. Inaddition, lungs can become stiff from hydrocarbon aspiration, smokeinhalation, and lung contusions. Fluorocarbon therapy can be providedeither as a surfactant supplement or for partial liquid breathing tosupply oxygen to a patient or to facilitate a therapeutic regime.Treatment of pulmonary fibrosis, emphysema, and chronic bronchitis canall benefit from fluorocarbon therapy.

It has been noted above that a fluorocarbon liquid may be supplied to apatient in combination with a powdered surfactant or as a route forpulmonary drug delivery. Antibiotics and antivirals may be provided incombination with a fluorocarbon liquid. For example, cytomegalovirus caninduce life-threatening cases of pneumonia in immunocompromisedpatients. These individuals often require ventilation therapy.Fluorocarbon administration in combination with the guanosine nucleosideanalog, 9-(1,3-dihydroxy-2-propoxymethyl)guanine otherwise known asGanciclovir or DHPG, may provide an effective therapy that couldsimultaneously inhibit viral replication and facilitate oxygen transportin the compromised lung.

In addition, anti-inflammatory agents could be added alone or incombination to the antimicrobial agents contemplated above. Theseanti-inflammatory agents include but are not limited to steroid andsteroid derivatives or analgesics. The fluorocarbon could beadministered together with a bronchodilator including but not limited toAlbuterol, Isoetharines, perbuteral or an anti-allergenic agent.

The various pharmaceuticals that can be combined with fluorocarbons toprovide therapy via administration to the lungs are too numerous tolist. Except in some particularly preferred embodiments listed herein,the choice of pharmaceutical is not critical. Any non-damagingpharmaceutical that can be adsorbed across the lung membranes, or thatcan treat lung tissue, can be used. The amounts and frequency ofadministration for all the various possible pharmaceuticals have beenestablished. It is not contemplated that these will be significantlydifferent for administration through use of fluorocarbon vehicles inpartial liquid breathing. Thus, those of ordinary skill in the art candetermine the proper amount of pharmaceutical and the timing of thedosages in accordance with already-existing information and withoutundue experimentation.

The fluorocarbon liquid may also be administered in combination with anantimitotic agent for cancer therapy. Fluorocarbon liquid can also beused to facilitate oxygenation under anesthesia for patient's sufferingfrom lung diseases such as emphysema, chronic bronchitis, and pulmonaryfibrosis. Furthermore, fluorocarbons can be used for partial liquidbreathing for any of the above mentioned maladies or any additionalmedical condition that would lend itself to this therapy.

The fluorocarbon liquid may advantageously be supplied to the physicianin a sterile prepackaged form. Aliquots of the fluorocarbon are removedfor administration under sterile conditions. Individual dosage volumescan be supplied for administration to newborns since newborn lungcapacities are within a fairly narrow range. For those applicationsrequiring a mixture of fluorocarbon and saline or powdered surfactant,each component can be provided separately and prepared for individualuse. For lavage purposes, neat fluorocarbon or prepared emulsions offluorocarbon and saline are provided prepackaged. It will be readilyappreciated that there are a large number of potential additives that,in combination with fluorocarbon liquid, have important medicalapplications in the lung.

Those with skill in the art will readily appreciate the variedapplications for fluorocarbon administration. Therefore the foregoingdetailed description is to be clearly understood as given by way ofillustration, the spirit and scope of this invention being limitedsolely by the appended claims.

What is claimed is:
 1. A method of facilitating oxygen delivery throughthe lung of a patient comprising the steps of:administering to the lungof the patient an effective oxygen delivery-facilitating amount of afluorocarbon liquid having an equilibrium coefficient of spreading whichis a positive number, said amount of administered fluorocarbon liquidnot exceeding 35% of the functional residual capacity of the lung of thepatient upon exhalation taking into account any positive or negativeexpiratory pressure applied to said patient's lung; and introducing abreathing gas into the lung wherein said introduced breathing gasphysically admixes with and oxygenates said fluorocarbon liquid withinthe lung.
 2. The method of claim 1 wherein said fluorocarbon liquidcomprises a mixture of two or more fluorocarbons.
 3. The method of claim2 wherein the mixture of fluorocarbons comprises at least onefluorocarbon having an equilibrium coefficient of spreading which is anegative number.
 4. The method of claim 1 wherein said fluorocarbonliquid further comprises a surfactant.
 5. The method of claim 1 whereinsaid fluorocarbon liquid comprises a fluorocarbon-hydrocarbon compound.6. The method of claim 1 wherein said fluorocarbon liquid comprisesperfluorooctylbromide.
 7. The method of claim 1 wherein saidfluorocarbon liquid has a surface tension value less than 20 dynes/cm.8. The method of claim 1 wherein said fluorocarbon liquid comprises anon-brominated fluorocarbon.
 9. The method of claim 8 wherein saidnon-brominated fluorocarbon is perfluorooctylethane.
 10. The method ofclaim 1 further comprising the step of introducing said breathing gas byspontaneous ventilation while the fluorocarbon liquid is in the lung.11. The method of claim 1 further comprising the step of introducingsaid breathing gas using mechanical ventilation while the fluorocarbonliquid is in the lung.
 12. The method of claim 1 wherein saidfluorocarbon liquid is administered as an aerosol.
 13. A method for thepulmonary administration of a pharmacologic agent to a patientcomprising:administering to the lung of the patient an effectivetherapeutic amount of a pharmacologic agent dispersed in a volume offluorocarbon liquid having an equilibrium coefficient of spreading whichis a positive number, said administered volume of fluorocarbon liquidnot exceeding 35% of the functional residual capacity of the lung of thepatient upon exhalation taking into account any positive or negativeexpiratory pressure applied to said patient's lung; and introducing abreathing gas into the lung wherein said introduced breathing gasphysically admixes with and oxygenates said fluorocarbon liquid withinthe lung.
 14. The method of claim 13 wherein said fluorocarbon liquidcomprises a mixture of two or more fluorocarbons.
 15. The method ofclaim 14 wherein the mixture of fluorocarbons comprises at least onefluorocarbon having an equilibrium coefficient of spreading which is anegative number.
 16. The method of claim 13 wherein said fluorocarbonliquid comprises perfluorooctylbromide.
 17. The method of claim 13wherein said fluorocarbon liquid comprises a fluorocarbon-hydrocarboncompound.
 18. The method of claim 13 wherein said fluorocarbon liquidcomprises a non-brominated fluorocarbon.
 19. The method of claim 18wherein said non-brominated fluorocarbon is perfluorooctylethane. 20.The method of claim 13 further comprising the step of introducing saidbreathing gas using spontaneous ventilation while the fluorocarbonliquid is in the lung.
 21. The method of claim 13 further comprising thestep of introducing said breathing gas using mechanical ventilationwhile the fluorocarbon liquid is in the lung.
 22. The method of claim 13wherein said pharmacologic agent is selected from the group consistingof bronchodilators, expectorants, lung surfactants, antibiotics,antivirals, anti-inflammatory agents, antimitotic agents, anestheticsand combinations thereof.
 23. A method of facilitating oxygen deliverythrough the lung of a patient comprising the steps of:administering tothe lung of the patient an effective oxygen delivery-facilitating amountof a non-brominated fluorocarbon liquid having an equilibriumcoefficient of spreading which is a positive number, said amount ofadministered non-brominated fluorocarbon liquid not exceeding thefunctional residual capacity of the lung of the patient upon exhalationtaking into account any positive or negative expiratory pressure appliedto said patient's lung; and introducing a breathing gas into the lungwherein said introduced breathing gas physically admixes with andoxygenates said non-brominated fluorocarbon liquid within the lung. 24.The method of claim 23 wherein said non-brominated fluorocarbon liquidcomprises a mixture of two or more non-brominated fluorocarbons.
 25. Themethod of claim 24 wherein the mixture of non-brominated fluorocarbonscomprises at least one non-brominated fluorocarbon having an equilibriumcoefficient of spreading which is a negative number.
 26. The method ofclaim 23 wherein said fluorocarbon liquid comprises afluorocarbon-hydrocarbon compound.
 27. The method of claim 23 whereinsaid non-brominated fluorocarbon liquid is a non-halogenatedfluorocarbon liquid.
 28. The method of claim 27 where saidnon-halogenated fluorocarbon liquid comprises perfluorooctylethane. 29.The method of claim 23 further comprising the step of introducing saidbreathing gas using spontaneous ventilation while the fluorocarbonliquid is in the lung.
 30. The method of claim 23 further comprising thestep of introducing said breathing gas using mechanical ventilationwhile the fluorocarbon liquid is in the lung.
 31. A method for removingmaterial from the lung of a patient comprising the stepsof:administering to the lung of the patient an effective materialdisplacing amount of a non-brominated fluorocarbon liquid having anequilibrium coefficient of spreading which is a positive number, saidamount of administered non-brominated fluorocarbon liquid not exceedingthe functional residual capacity of the lung of the patient uponexhalation taking into account any positive or negative expiratorypressure applied to said patient's lung wherein the administerednon-brominated fluorocarbon liquid displaces material inside the lung;introducing a breathing gas while the non-brominated fluorocarbon liquidis in the lung; and removing said non-brominated fluorocarbon liquidtogether with at least a portion of the displaced material from thelung.
 32. The method of claim 31 wherein said non-brominatedfluorocarbon liquid comprises a mixture of two or more non-brominatedfluorocarbons.
 33. The method of claim 32 wherein the mixture ofnon-brominated fluorocarbons comprises at least one non-brominatedfluorocarbon having an equilibrium coefficient of spreading which is anegative number.
 34. The method of claim 31 wherein said fluorocarbonliquid comprises a fluorocarbon-hydrocarbon compound.
 35. The method ofclaim 31 wherein said non-brominated fluorocarbon liquid is anon-halogenated fluorocarbon liquid.
 36. The method of claim 35 wheresaid non-halogenated fluorocarbon liquid comprises perfluorooctylethane.37. The method of claim 31 further comprising the step of introducingsaid breathing gas using spontaneous ventilation.
 38. The method ofclaim 31 further comprising the step of introducing said breathing gasusing mechanical ventilation.
 39. The method of claim 31 wherein thedisplaced material is selected from the group consisting of aspiratedmeconium, lung cells, exudate, irritants, poisons, mucous plugs, foodaspirates and adventitious agents.
 40. A method of facilitating oxygendelivery through the lung of a patient comprising the stepsof:administering to the lung of the patient an effective oxygendelivery-facilitating amount of a fluorocarbon liquid having anequilibrium coefficient of spreading which is a positive number andcomprising fluorocarbons selected from the group consisting ofbis(F-alkyl) ethanes, cyclic fluorocarbons, fluorinated amines,fluorocarbon esters, fluorocarbon thioesters, perfluoroalkylated ethers,perfluoroalkylated polyethers and fluorocarbon-hydrocarbon compounds,said amount of administered fluorocarbon liquid not exceeding thefunctional residual capacity of the lung of the patient upon exhalationtaking into account any positive or negative expiatory pressure appliedto said patient's lung; and introducing a breathing gas into the lungwherein said introduced breathing gas physically admixes with andoxygenates said non-brominated fluorocarbon liquid within the lung. 41.The method of claim 40 wherein said fluorocarbon liquid comprises acyclic fluorocarbon selected from the group consisting ofperfluorodecalin, F-adamantane, F-methyladamantane, F-1,3-dimethyladamantane, F-dimethylbicyclo[3,3,1]nonane,F-dimethylbicyclo[3,3,1]nonane and combinations thereof.
 42. The methodof claim 40 wherein said fluorocarbon liquid comprises a perfluorinatedamine selected from the group consisting of F-tripropylamine,F-tri-butylamine, F-4-methyloctahydroquinolizine,F-n-methyl-decahydroisoquinoline, F-n-methyldecahydroquinoline,F-n-cyclohexylpurrolidine, F-2-butyltetrahydrofuran and combinationsthereof.
 43. The method of claim 40 further comprising the step ofintroducing said breathing gas using spontaneous ventilation while thenon-brominated fluorocarbon liquid is in the lung.
 44. The method ofclaim 40 further comprising the step of introducing said breathing gasusing mechanical ventilation while the non-brominated fluorocarbonliquid is in the lung.